A Real Mindbender

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Baby neurons (green) attached to the terminals of interneurons (orange).

In our adult brains, right now, new neurons are being born. That’s the good news; a healthy brain needs all the neurons it can get. The bad news is that most of those baby neurons die before they could help with cognition, memory, or the regulation of mood.

Why most new neurons die while a few survive has been a mystery. But now, UNC School of Medicine neuroscientist Juan Song has some answers. Her study, published in the journal Nature Neuroscience, is the first to show how specific brain cells communicate with each other during adult neurogenesis – the creation of new neurons. She also found that one cell type – PV+ interneurons – can be stimulated to help baby neurons survive and thrive even as older neurons die.

“We now know how newborn neurons can be regenerated in specific regions of the brain,” said Song, assistant professor in the department of pharmacology and the UNC Neuroscience Center. The finding has wide implications for people with neurodegenerative conditions, such as dementia or Alzheimer’s disease, and perhaps for patients with brain damage. “By showing how interneurons are a part of neurogenesis, we can see how it’s possible to regenerate cells in parts of the brain that are damaged, for example, because of a stroke.”

Neurogenesis, which occurs throughout the brain during pre-natal development, continues throughout adulthood in just two brain regions – the hippocampus and subventricular zone.

It works like this: neural stem cells produce progenitor cells, more than half of which die within four days. The progenitor cells don’t have axons or dendrites – the cell parts that adult neurons use to create and transmit signals to each other.

The surviving progenitor cells – also known as newborn or baby neurons – then turn into immature neurons; these do form axons and dendrites and evolve into mature neurons that connect with other neurons through synapses. These mature neurons then integrate into the complex neural networks involved in cognition, memory, and mood.

Previously, when Song was a postdoctoral fellow at Johns Hopkins University, she studied how stem cells create neurons. She was first author and lead researcher of a study published in Nature that showed how neural stem cells “sense” the transmission of chemical signals between mature neurons and PV+ interneurons.

Song’s team used words such as “sensed” and “listened” and “eavesdropped” because they found that the stem cells did not form synaptic connections with either the mature neurons or the interneurons. They somehow “heard” the chemical signaling between the two other cell types. And depending on the signal, the stem cells either stayed dormant or began creating progenitor cells.

Because Song found that the stem cells weren’t physically connected to interneurons or mature neurons, she thought that the stem cell progeny – the newborn neurons – might also “sense” the chemical communication between mature neurons and interneurons. But that’s not what she found.

Using mouse models and electron microscopy, Song discovered that PV+ interneurons attach their tail-like axons to newborn progenitor cells to form a synapse. Across that synaptic connection, the interneurons send chemical signals.

When Song stimulated the interneurons with a beam of light or mild electrical signals, the baby neurons lived longer than they did without stimulation.

“The progenitors survived,” Song said. “They evolved into new neurons. So, this stimulation created more neurogenesis in the adult brains of mice.”

It’s unclear how such stimulation translates into human activity. For instance, exercise has been found to trigger the creation of neurons in mice. And exercise in adults has shown to improve brain function. But it isn’t clear that the creation of new neurons always causes improved brain function. Also, it isn’t clear that the lack of exercise – both physical and perhaps cognitive – slows down neurogenesis as we age.

Still, Song’s research is the first to show that simulating a specific cell type does indeed spur on neurogenesis. The finding underscores the importance of a specific cell type – PV+ interneurons – in the creation of new neurons, and it offers researchers another route to finding therapies for degenerative conditions and even brain disorders, such as schizophrenia.

“I think our study could be extended to look directly at behaviors in mouse models of neurological diseases,” Song said. “We would be able to see if behaviors are linked to interneurons and neurogenesis.”

For now, Song’s lab is still uncovering the mysteries of neurogenesis in normal animal models. For instance, scientists aren’t sure exactly how stem cells “sense” the communication between interneurons and mature neurons. They also don’t know if simply stimulating interneurons causes stem cells to give birth to progenitor cells or if something more complicated is going on. Song is studying that now.

Her team also wants to study exactly how interneurons become attached to progenitor cells; how do interneurons “find” the baby neurons to communicate with them?

“Right now, we don’t know,” Song said. “Our working hypothesis is that new neurons are born into a mesh of interneuron terminals. And we think the newborn neurons possess chemical signals that guide the interneurons, which then attach to the newborn neurons.

“It would be interesting to see if the newborn neurons that lack this synaptic connection are the same ones that die before becoming mature neurons.”

If that’s the case, it would be the first explanation for why more than half of our baby neurons die before they can help us ward off some of the cognitive deficits we experience as we age and, in some cases, the extreme symptoms we see in degenerative conditions and brain disorders.

Juan Song is an assistant professor in the department of pharmacology in the UNC School of medicine and also a primary member in the UNC Neurosciences Center. Her collaborators include senior author of the Nature Neuroscience paper Hongjun Song, Guo-li Ming, Jiaqi Sun, Zhexing Wen, Gerald J. Sun, Derek Hsu, Chun Zhong, and Heydar Davoudi, and Kimberly Christian of Johns Hopkins, and Jonathan Moss and Nicolas Toni of the University of Lausanne in Switzerland. The study was funded by the National Institutes of Health, the Miriam and Sheldon G. Adelson Medical Research Foundation, The Brain and Behavior Research Foundation, the Maryland Stem Cell Research Fund, the Swiss National Science Foundation, and the Fondation Leenards in Switzerland.